tbuckley/cabot-search huggingface dataset:
The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy
Authors: Keli Lima, Diego Antonio Pereira-Martins, Lívia Bassani Lins de Miranda, Juan Luiz Coelho-Silva, Giovana da Silva Leandro, Isabel Weinhäuser, Rita de Cássia Cavaglieri, Aline de Medeiros Leal, Wellington Fernandes da Silva, Ana Paula Alencar de Lima Lange, Elvira Deolinda Rodrigues Pereira Velloso, Emmanuel Griessinger, Jacobien R. Hilberink, Emanuele Ammatuna, Gerwin Huls, Jan Jacob Schuringa, Eduardo Magalhães Rego, João Agostinho Machado-Neto
Journal: Blood Cancer Journal (2022)

Abstract The treatment of acute leukemia is challenging because of the genetic heterogeneity between and within patients. Leukemic stem cells (LSCs) are relatively drug-resistant and frequently relapse. Their plasticity and capacity to adapt to extracellular stress, in which mitochondrial metabolism and autophagy play important roles, further complicates treatment. Genetic models of phosphatidylinositol-5-phosphate 4-kinase type 2 protein (PIP4K2s) inhibition have demonstrated the relevance of these enzymes in mitochondrial homeostasis and autophagic flux. Here, we uncovered the cellular and molecular effects of THZ-P1-2, a pan-inhibitor of PIP4K2s, in acute leukemia cells. THZ-P1-2 reduced cell viability and induced DNA damage, apoptosis, loss of mitochondrial membrane potential, and the accumulation of acidic vesicular organelles. Protein expression analysis revealed that THZ-P1-2 impaired autophagic flux. In addition, THZ-P1-2 induced cell differentiation and showed synergistic effects with venetoclax. In primary leukemia cells, LC-MS/MS-based proteome analysis revealed that sensitivity to THZ-P1-2 is associated with mitochondrial metabolism, cell cycle, cell-of-origin (hematopoietic stem cell and myeloid progenitor), and the TP53 pathway. The minimal effects of THZ-P1-2 observed in healthy CD34 + cells suggest a favorable therapeutic window. Our study provides insights into the pharmacological inhibition of PIP4K2s targeting mitochondrial homeostasis and autophagy, shedding light on a new class of drugs for acute leukemia.
Introduction of monkeypox virus in Benin, 2022
Authors: Anges Yadouleton, Martin Faye, Carine Tchibozo, Mariam Oke, Oumar Faye, Thierry Lawale, Eric Denon, René Keke, Ange Dossou, Alban Zohoun, Francis Dossou, Moussa Moise Diagne, Sourakou Salifou, Khadija Leila Diatta, Mignane Ndiaye, Safietou Sankhe, Amadou Diallo, Sonia Bedie, Clément Glele-Kakai, Al Fattah Onifade, Raoul Saizonou, Gildas Hounkanrin, Olga Quenum, Yvette Badou, Benjamin Hounkpatin, Amadou Alpha Sall, Ousmane Faye
Journal: Military Medical Research (2022)
Retinoid X receptor promotes hematopoietic stem cell fitness and quiescence and preserves hematopoietic homeostasis
Authors: María Piedad Menéndez-Gutiérrez, Jesús Porcuna, Ramesh Nayak, Ana Paredes, Haixia Niu, Vanessa Núñez, Aditi Paranjpe, Manuel J. Gómez, Anukana Bhattacharjee, Daniel J. Schnell, Fátima Sánchez-Cabo, John S. Welch, Nathan Salomonis, Jose A. Cancelas, Mercedes Ricote
Journal: Blood (2022)

Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain hematopoietic fitness throughout life. In steady-state conditions, HSC exhaustion is prevented by the maintenance of most HSCs in a quiescent state, with cells entering the cell cycle only occasionally. HSC quiescence is regulated by retinoid and fatty-acid ligands of transcriptional factors of the nuclear retinoid X receptor (RXR) family. Herein, we show that dual deficiency for hematopoietic RXRα and RXRβ induces HSC exhaustion, myeloid cell/megakaryocyte differentiation, and myeloproliferative-like disease. RXRα and RXRβ maintain HSC quiescence, survival, and chromatin compaction; moreover, transcriptome changes in RXRα;RXRβ-deficient HSCs include premature acquisition of an aging-like HSC signature, MYC pathway upregulation, and RNA intron retention. Fitness loss and associated RNA transcriptome and splicing alterations in RXRα;RXRβ-deficient HSCs are prevented by Myc haploinsufficiency. Our study reveals the critical importance of RXRs for the maintenance of HSC fitness and their protection from premature aging.
Trace amine-associated receptor 1 (TAAR1) agonism as a new treatment strategy for schizophrenia and related disorders
Authors: Els F. Halff, Grazia Rutigliano, Anna Garcia-Hidalgo, Oliver D. Howes
Journal: Trends in Neurosciences (2022)

Schizophrenia remains a major health burden, highlighting the need for new treatment approaches. We consider the potential for targeting the trace amine (TA) system. We first review genetic, preclinical, and clinical evidence for the role of TAs in the aetiopathology of schizophrenia. We then consider how the localisation and function of the trace amine-associated receptor 1 (TAAR1) position it to modulate key brain circuits for the disorder. Studies in rodents using Taar1 knockout (TAAR1-KO) and overexpression models show that TAAR1 agonism inhibits midbrain dopaminergic and serotonergic activity, and enhances prefrontal glutamatergic function. TAAR1 agonists also reduce hyperactivity, attenuate prepulse inhibition (PPI) deficits and social withdrawal, and improve cognitive measures in animal models. Finally, we consider findings from clinical trials of TAAR1 agonists and how this approach may address psychotic and negative symptoms, tolerability issues, and other unmet needs in the treatment of schizophrenia.
Correction: Translatome proteomics identifies autophagy as a resistance mechanism to on-target FLT3 inhibitors in acute myeloid leukemia
Authors: Sebastian E. Koschade, Kevin Klann, Shabnam Shaid, Binje Vick, Jan A. Stratmann, Marlyn Thölken, Laura M. Meyer, The Duy Nguyen, Julia Campe, Laura M. Moser, Susanna Hock, Fatima Baker, Christian T. Meyer, Frank Wempe, Hubert Serve, Evelyn Ullrich, Irmela Jeremias, Christian Münch, Christian H. Brandts
Journal: Leukemia (2022)
Impact of radiographer immediate reporting of X-rays of the chest from general practice on the lung cancer pathway (radioX): a randomised controlled trial
Authors: Nick Woznitza, Bhagabati Ghimire, Anand Devaraj, Sam M Janes, Keith Piper, Susan Rowe, Angshu Bhowmik, Natasha Hayes, Daniel Togher, Nikita Arumalla, Erik Skyllberg, Iain T H Au-Yong, Susan Geary, Bindu George, Sarah Sheard, Stephen Ellis, Zoheb Shah, Sue Maughn, Stephen W Duffy, David Baldwin
Journal: Thorax (2022)

The National Optimal Lung Cancer Pathway recommends rapid progression from abnormal chest X-rays (CXRs) to CT. The impact of the more rapid reporting on the whole pathway is unknown. The aim of this study was to determine the impact of immediate reporting of CXRs requested by primary care by radiographers on the time to diagnosis of lung cancer.People referred for CXR from primary care to a single acute district general hospital in London attended sessions that were prerandomised to either immediate radiographer (IR) reporting or standard radiographer (SR) reporting within 24 hours. CXRs were subsequently reported by radiologists blind to the radiographer reports to test the reliability of the radiographer report. Radiographer and local radiologist discordant cases were reviewed by thoracic radiologists, blinded to reporter.8682 CXRs were performed between 21 June 2017 and 4 August 2018, 4096 (47.2%) for IR and 4586 (52.8%) for SR. Lung cancer was diagnosed in 49, with 27 (55.1%) for IR. The median time from CXR to diagnosis of lung cancer for IR was 32 days (IQR 19, 70) compared with 63 days (IQR 29, 78) for SR (p=0.03).8258 CXRs (95.1%) were reported by both radiographers and local radiologists. In the 1361 (16.5%) with discordance, the reviewing thoracic radiologists were equally likely to agree with local radiologist and radiographer reports.Immediate reporting of CXRs from primary care reduces time to diagnosis of lung cancer by half, likely due to rapid progress to CT. Radiographer reports are comparable to local radiologist reports for accuracy.International Standard Randomised Controlled Trial Number ISRCTN21818068. Registered on 20 June 2017.
Genetic basis and molecular profiling in myeloproliferative neoplasms
Authors: Damien Luque Paz, Robert Kralovics, Radek C. Skoda
Journal: Blood (2022)

BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are clonal diseases originating from a single hematopoietic stem cell that cause excessive production of mature blood cells. The 3 subtypes, that is, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are diagnosed according to the World Health Organization (WHO) and international consensus classification (ICC) criteria. Acquired gain-of-function mutations in 1 of 3 disease driver genes (JAK2, CALR, and MPL) are the causative events that can alone initiate and promote MPN disease without requiring additional cooperating mutations. JAK2-p.V617F is present in >95% of PV patients, and also in about half of the patients with ET or PMF. ET and PMF are also caused by mutations in CALR or MPL. In ∼10% of MPN patients, those referred to as being "triple negative," none of the known driver gene mutations can be detected. The common theme between the 3 driver gene mutations and triple-negative MPN is that the Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway is constitutively activated. We review the recent advances in our understanding of the early events after the acquisition of a driver gene mutation. The limiting factor that determines the frequency at which MPN disease develops with a long latency is not the acquisition of driver gene mutations, but rather the expansion of the clone. Factors that control the conversion from clonal hematopoiesis to MPN disease include inherited predisposition, presence of additional mutations, and inflammation. The full extent of knowledge of the mutational landscape in individual MPN patients is now increasingly being used to predict outcome and chose the optimal therapy.
ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Authors: Ana-Caroline Raulin, Sydney V. Doss, Zachary A. Trottier, Tadafumi C. Ikezu, Guojun Bu, Chia-Chen Liu
Journal: Molecular Neurodegeneration (2022)

Alzheimer's disease (AD) is the most common cause of dementia worldwide, and its prevalence is rapidly increasing due to extended lifespans. Among the increasing number of genetic risk factors identified, the apolipoprotein E (APOE) gene remains the strongest and most prevalent, impacting more than half of all AD cases. While the ε4 allele of the APOE gene significantly increases AD risk, the ε2 allele is protective relative to the common ε3 allele. These gene alleles encode three apoE protein isoforms that differ at two amino acid positions. The primary physiological function of apoE is to mediate lipid transport in the brain and periphery; however, additional functions of apoE in diverse biological functions have been recognized. Pathogenically, apoE seeds amyloid-β (Aβ) plaques in the brain with apoE4 driving earlier and more abundant amyloids. ApoE isoforms also have differential effects on multiple Aβ-related or Aβ-independent pathways. The complexity of apoE biology and pathobiology presents challenges to designing effective apoE-targeted therapeutic strategies. This review examines the key pathobiological pathways of apoE and related targeting strategies with a specific focus on the latest technological advances and tools.
COVID-19 deaths in children and young people in England, March 2020 to December 2021: An active prospective national surveillance study
Authors: Marta Bertran, Zahin Amin-Chowdhury, Hannah G. Davies, Hester Allen, Tom Clare, Chloe Davison, Mary Sinnathamby, Giulia Seghezzo, Meaghan Kall, Hannah Williams, Nick Gent, Mary E. Ramsay, Shamez N. Ladhani, Godwin Oligbu
Journal: PLoS Medicine (2022)

Coronavirus Disease 2019 (COVID-19) deaths are rare in children and young people (CYP). The high rates of asymptomatic and mild infections complicate assessment of cause of death in CYP. We assessed the cause of death in all CYP with a positive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) test since the start of the pandemic in England.CYP aged <20 years who died within 100 days of laboratory-confirmed SARS-CoV-2 infection between 01 March 2020 and 31 December 2021 in England were followed up in detail, using national databases, surveillance questionnaires, post-mortem reports, and clinician interviews. There were 185 deaths during the 22-month follow-up and 81 (43.8%) were due to COVID-19. Compared to non-COVID-19 deaths in CYP with a positive SARS-CoV-2 test, death due to COVID-19 was independently associated with older age (aOR 1.06 95% confidence interval (CI) 1.01 to 1.11, p = 0.02) and underlying comorbidities (aOR 2.52 95% CI 1.27 to 5.01, p = 0.008), after adjusting for age, sex, ethnicity group, and underlying conditions, with a shorter interval between SARS-CoV-2 testing and death. Half the COVID-19 deaths (41/81, 50.6%) occurred within 7 days of confirmation of SARS-CoV-2 infection and 91% (74/81) within 30 days. Of the COVID-19 deaths, 61 (75.3%) had an underlying condition, especially severe neurodisability (n = 27) and immunocompromising conditions (n = 12). Over the 22-month surveillance period, SARS-CoV-2 was responsible for 1.2% (81/6,790) of all deaths in CYP aged <20 years, with an infection fatality rate of 0.70/100,000 SARS-CoV-2 infections in this age group estimated through real-time, nowcasting modelling, and a mortality rate of 0.61/100,000. Limitations include possible under-ascertainment of deaths in CYP who were not tested for SARS-CoV-2 and lack of direct access to clinical data for hospitalised CYP.COVID-19 deaths remain extremely rare in CYP, with most fatalities occurring within 30 days of infection and in children with specific underlying conditions.
Evaluation of physical activity calorie equivalent (PACE) labels’ impact on energy purchased in cafeterias: A stepped-wedge randomised controlled trial
Authors: James P. Reynolds, Minna Ventsel, Alice Hobson, Mark A. Pilling, Rachel Pechey, Susan A. Jebb, Gareth J. Hollands, Theresa M. Marteau
Journal: PLoS Medicine (2022)

A recent meta-analysis suggested that using physical activity calorie equivalent (PACE) labels results in people selecting and consuming less energy. However, the meta-analysis included only 1 study in a naturalistic setting, conducted in 4 convenience stores. We therefore aimed to estimate the effect of PACE labels on energy purchased in worksite cafeterias in the context of a randomised study design.A stepped-wedge randomised controlled trial (RCT) was conducted to investigate the effect of PACE labels (which include kcal content and minutes of walking required to expend the energy content of the labelled food) on energy purchased. The setting was 10 worksite cafeterias in England, which were randomised to the order in which they introduced PACE labels on selected food and drinks following a baseline period. There were approximately 19,000 workers employed at the sites, 72% male, with an average age of 40. The study ran for 12 weeks (06 April 2021 to 28 June 2021) with over 250,000 transactions recorded on electronic tills. The primary outcome was total energy (kcal) purchased from intervention items per day. The secondary outcomes were: energy purchased from non-intervention items per day, total energy purchased per day, and revenue. Regression models showed no evidence of an overall effect on energy purchased from intervention items, -1,934 kcals per site per day (95% CI -5,131 to 1,262), p = 0.236, during the intervention relative to baseline, equivalent to -5 kcals per transaction (95% CI -14 to 4). There was also no evidence for an effect on energy purchased from non-intervention items, -5 kcals per site per day (95% CI -513 to 504), p = 0.986, equivalent to 0 kcals per transaction (95% CI -1 to 1), and no clear evidence for total energy purchased -2,899 kcals per site (95% CI -5,810 to 11), p = 0.051, equivalent to -8 kcals per transaction (95% CI -16 to 0). Study limitations include using energy purchased and not energy consumed as the primary outcome and access only to transaction-level sales, rather than individual-level data.Overall, the evidence was consistent with PACE labels not changing energy purchased in worksite cafeterias. There was considerable variation in effects between cafeterias, suggesting important unmeasured moderators.The study was prospectively registered on ISRCTN (date: 30.03.21; ISRCTN31315776).
Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial
Authors: Ruth L Goodall, Sarah K Meredith, Andrew J Nunn, Adamu Bayissa, Anuj K Bhatnagar, Gay Bronson, Chen-Yuan Chiang, Francesca Conradie, Meera Gurumurthy, Bruce Kirenga, Nana Kiria, Daniel Meressa, Ronelle Moodliar, Gopalan Narendran, Nosipho Ngubane, Mohammed Rassool, Karen Sanders, Rajesh Solanki, S Bertel Squire, Gabriela Torrea, Bazarragchaa Tsogt, Elena Tudor, Armand Van Deun, I D Rusen, Oyunchimeg Adilaa, Sofia Alexandru, Katharine Bellenger, Jaclyn Bennet, Deborah Bennet, Priyanka Bindroo, Ghanshyam Borisagar, Claire Cook, Doljinsuren Dalai, Andrew Davis, Bouke de Jong, Wendy Dodds, Lynette Duckworth, Nonhlanhla Gahima, Belay Gebreegziabher, Anne Goldfeld, Mahmud Hanifa, Gareth Hughes, Ivan Kimuli, Jan Komrska, Nino Lomtadze, Brendan Murphy, Thando Mwelase, Joanitah Nalunjogi, Leena Patel, Irina Pirlog, Ishmael Qawiy, Mary Rauchenberger, Leen Rigouts, Carol Roach, Laura Rosu, Ezio Santos-Filho, Thirumaran Senguttuvan, Million Sisay, Rathinam Sridhar, Vignes Srinivasulu, Mekonnen Teferi, Helen Teklu, Narangarav Tsegeen, Odette van Amsterdam, Lisa White, Johanna Whitney, Chuluunbaatar Zagd
Journal: The Lancet (2022)
Evolution and function of developmentally dynamic pseudogenes in mammals
Authors: Sheng Hu Qian, Lu Chen, Yu-Li Xiong, Zhen-Xia Chen
Journal: Genome biology (2022)

Abstract Background Pseudogenes are excellent markers for genome evolution, which are emerging as crucial regulators of development and disease, especially cancer. However, systematic functional characterization and evolution of pseudogenes remain largely unexplored. Results To systematically characterize pseudogenes, we date the origin of human and mouse pseudogenes across vertebrates and observe a burst of pseudogene gain in these two lineages. Based on a hybrid sequencing dataset combining full-length PacBio sequencing, sample-matched Illumina sequencing, and public time-course transcriptome data, we observe that abundant mammalian pseudogenes could be transcribed, which contribute to the establishment of organ identity. Our analyses reveal that developmentally dynamic pseudogenes are evolutionarily conserved and show an increasing weight during development. Besides, they are involved in complex transcriptional and post-transcriptional modulation, exhibiting the signatures of functional enrichment. Coding potential evaluation suggests that 19% of human pseudogenes could be translated, thus serving as a new way for protein innovation. Moreover, pseudogenes carry disease-associated SNPs and conduce to cancer transcriptome perturbation. Conclusions Our discovery reveals an unexpectedly high abundance of mammalian pseudogenes that can be transcribed and translated, and these pseudogenes represent a novel regulatory layer. Our study also prioritizes developmentally dynamic pseudogenes with signatures of functional enrichment and provides a hybrid sequencing dataset for further unraveling their biological mechanisms in organ development and carcinogenesis in the future.
Discriminating activities of DEAD-Box Helicase 41 from myeloid malignancy-associated germline variants by genetic rescue
Authors: Jeong-Ah Kim, Siqi Shen, Daniel R. Matson, Lauren N. Lovrien, Kelcy J. Smith-Simmer, Sunduz Keles, Jane E. Churpek, Emery H. Bresnick
Journal: Leukemia (2022)
Trends in hospital admissions during transition from paediatric to adult services for young people with learning disabilities or autism: population-based cohort study
Authors: Ania Zylbersztejn, Philippa Anna Stilwell, Hannah Zhu, Viki Ainsworth, Janice Allister, Karen Horridge, Terence Stephenson, Linda Wijlaars, Ruth Gilbert, Michelle Heys, Pia Hardelid
Journal: The Lancet Regional Health - Europe (2022)

Transition from paediatric to adult health care may disrupt continuity of care, and result in unmet health needs. We describe changes in planned and unplanned hospital admission rates before, during and after transition for young people with learning disability (LD), or autism spectrum disorders (ASD) indicated in hospital records, who are likely to have more complex health needs.We developed two mutually exclusive cohorts of young people with LD, and with ASD without LD, born between 1990 and 2001 in England using national hospital admission data. We determined the annual rate of change in planned and unplanned hospital admission rates before (age 10-15 years), during (16-18 years) and after (19-24 years) transition to adult care using multilevel negative binomial regression models, accounting for area-level deprivation, sex, birth year and presence of comorbidities.The cohorts included 51,291 young people with LD, and 46,270 autistic young people. Admission rates at ages 10-24 years old were higher for young people with LD (54 planned and 25 unplanned admissions per 100 person-years) than for autistic young people (17/100 and 16/100, respectively). For young people with LD, planned admission rates were highest and constant before transition (rate ratio [RR]: 0.99, 95% confidence interval [CI] 0.98-0.99), declined by 14% per year of age during (RR: 0.86, 95% CI: 0.85-0.88), and remained constant after transition (RR: 0.99, 95% CI: 0.99-1.00), mainly due to fewer admissions for non-surgical care, including respite care. Unplanned admission rates increased by 3% per year of age before (RR: 1.03, 95% CI: 1.02-1.03), remained constant during (RR: 1.01, 95% CI: 1.00-1.03) and increased by 3% per year after transition (RR: 1.03, 95% CI: 1.02-1.04). For autistic young people, planned admission rates increased before (RR: 1.06, 95% CI: 1.05-1.06), decreased during (RR: 0.95, 95% CI: 0.93-0.97), and increased after transition (RR: 1.05, 95%: 1.04-1.07). Unplanned admission rates increased most rapidly before (RR: 1.16, 95% CI: 1.15-1.17), remained constant during (RR: 1.01, 95% CI: 0.99-1.03), and increased moderately after transition (RR: 1.03, 95% CI: 1.02-1.04).Decreases in planned admission rates during transition were paralleled by small but consistent increases in unplanned admission rates with age for young people with LD and autistic young people. Decreases in non-surgical planned care during transition could reflect disruptions to continuity of planned/respite care or a shift towards provision of healthcare in primary care and community settings and non-hospital arrangements for respite care.National Institute for Health Research Policy Research Programme.